The researchers, led by the Mayo Clinic in Florida, discovered a short DNA sequence repeated hundreds to thousands of times in almost 12 percent of familial FTD and more than 22 percent of familial ALS of samples studied.
Their findings are published in the September 21 online issue of Neuron.
“This is the most common genetic defect, in both familial and sporadic cases, identified to date in these two different, but equally devastating neurodegenerative conditions, and confirms an overlap between FTD and ALS at the molecular level,” says Ian Mackenzie, a professor in the dept. of pathology and laboratory medicine at UBC.
After Alzheimer’s disease, FTD is the second most common form of early onset neurodegenerative dementia. It is characterized by changes in personality, behaviour and language due to loss of gray matter in the brain’s frontal and temporal lobes. ALS destroys motor neuron cells that control essential muscle activity such as speaking, walking, breathing and swallowing.
Researchers have recently found similarity between the two disorders: Up to half of ALS patients experience symptoms of FTD, and, similarly, up to half of FTD patients develop clinical symptoms of motor neuron dysfunction seen in ALS. Both diseases can also occur in the same family and post mortem examination often shows abnormal accumulation of the same proteins in the brain.
The abnormally expanded repeat of C and G (two of the four nucleotides that make up the genetic code) was found in a gene on chromosome 9 called C9ORF72, which encodes a protein whose normal function and role in disease are currently unknown. However, the researchers – led by the Mayo Clinic’s Rosa Rademakers — found evidence that when the defective gene is transcribed into a messenger RNA molecule, the expanded repeat section accumulates in cells and binds tightly to other critical proteins, thus preventing them from carrying out their normal cellular functions.
Dr. Mackenzie’s research team, at the Brain Research Centre at Vancouver Coastal Health (VCH) and UBC, provided genetic samples from a number of British Columbia families with FTD and ALS, and identified a pattern of pathology in the post mortem brain tissue of patients that accurately predicted the presence of the mutation. As a result, the collection of cases provided by Vancouver researchers had the highest frequency of the mutation (62 per cent).
In addition, Dr. Mackenzie played a key role in defining the impact of the mutation on brain cells by demonstrating abnormal patterns of protein expression and the presence of the potentially toxic accumulations of mutant RNA.
“The data we obtained from our UBC Hospital families was instrumental to this study,” Dr. Mackenzie says. “It provided us crucial understanding of the mechanism of brain injury and potential avenues for therapeutic intervention.”
This finding will aid in genetic counseling for affected families, and in the longer term, will be crucial for the development of new treatments.
This is one of several successful collaborations between Dr. Mackenzie’s VCH and UBC team and the Mayo Clinic around the causes of FTD. In 2006, they discovered mutations in a different gene (called progranulin) to be another important cause of familial FTD.
The FTD research program at UBC and VCH is supported by funding from the Canadian Institutes of Health Research and the Pacific Alzheimer’s Research Foundation.
The UBC Faculty of Medicine provides innovative programs in the health and life sciences, teaching students at the undergraduate, graduate and postgraduate levels. Its faculty members received $295 million in research funds, 54 percent of UBC’s total research revenues, in 2010-11. For more information, visit www.med.ubc.ca
The Vancouver Coastal Health Research Institute (VCHRI) is the research body of Vancouver Coastal Health Authority, which includes BC’s largest academic and teaching health sciences centres: VGH, UBC Hospital, and GF Strong Rehabilitation Centre. In academic partnership with the University of British Columbia, VCHRI brings innovation and discovery to patient care, advancing healthier lives in healthy communities across British Columbia, Canada, and beyond. www.vchri.ca.
The Brain Research Centre comprises more than 200 investigators with multidisciplinary expertise in neuroscience research ranging from the test tube, to the bedside, to industrial spin-offs. The centre is a partnership of UBC and VCH Research Institute. For more information, visit www.brain.ubc.ca.